Porphyrins bearing only one or two substituents present a compact architecture suitable for a wide variety of applications or further synthetic elaboration. For substituents at the meso-positions, the methodology established for preparing porphyrins bearing four distinct meso-substituents would appear applicable. The route to such ABCD-porphyrins entails condensation of a dipyrromethane+dipyrromethane-1,9-dicarbinol, where the four substituents are introduced via the meso-positions of both dipyrromethane species and the carbinol units at the 1- and 9-positions.1 The corresponding synthesis of A-porphyrins, trans-AB-porphyrins, (and also trans-A2-porphyrins)2 would employ meso-substituted dipyrromethanes with no substituents at the carbinol sites. To our surprise, condensations with dipyrromethanes bearing primary carbinol groups proceeded poorly, giving a mixture of porphyrins and overall low yields.3. No better alternatives (other than statistical condensations) to A-porphyrins or trans-AB-porphyrins have been developed. This limitation prompted us to investigate C1 synthons having greater reactivity than primary carbinol groups for the rational synthesis of porphyrins bearing one or two meso-substituents.
A wide variety of C1 synthons have been employed in porphyrin chemistry, either as functional groups (aldehyde,4 hydroxymethyl3) attached to a pyrrolic species or as added reagents (formic acid,5 trimethyl orthoformate,5,6 formaldehyde,7 and imines8). A key consideration in the use of dipyrromethanes is the possibility of acidolysis followed by undesired recombination of dipyrromethane-derived fragments, affording undesired porphyrin species (i.e., scrambling). The possibility of scrambling constrains the nature of the reactive groups employed as C1 synthons (e.g., aldehyde or hydroxymethyl) and reaction conditions that can be employed.
The aminomethyl group is an attractive candidate for the C1 synthon leading to porphyrinic macrocycles because of ease of introduction, the possibility that reaction can be carried out without added acid catalysts, and biomimetic analogy. Indeed, an aminomethylpyrrole (porphobilinogen, A)9 is the biosynthetic precursor of all naturally occurring porphyrinic macrocycles (Chart 1). Aminomethylpyrroles have been prepared by the condensation of pyrrole derivatives with aldehydes and amines.10 The advent of N,N-dimethylmethyleneammonium iodide (Eschenmoser's reagent),11 designed for reactions with corrins, also facilitated the synthesis of aminomethylpyrrolic compounds. To construct porphyrinic macrocycles from aminomethylpyrroles, three different approaches have been investigated: (1) self-condensation of an aminomethylpyrrole (e.g., B or C),12 (2) condensation of a bis(aminomethyl)pyrrole (e.g., D or E) with a pyrrole derivative,12-14 and (3) 3+1 condensation of a bis(aminomethyl)pyrrole D with a tripyrrane.14,15 These approaches are attractive in their simplicity but have the potential limitation of forming a mixture of porphyrin regioisomers depending on the β-substitution pattern of the pyrrolic substrates.

Although aminomethyl-dipyrromethanes can be attractive precursors for porphyrinic macrocycles, aminomethyl-dipyrromethane derivatives (F) have been mainly used for the synthesis of expanded porphyrins, such as porphocyanine.16 To our knowledge, the only previous example of aminomethyl-dipyrromethane derivatives in porphyrin chemistry is Hombrecher's synthesis of meso-substituted etioporphyrins:17 treatment of a dipyrromethane with a Mannich reagent (CH2═NEt2Cl) gave the 1,9-bis(N,N-diethylaminomethyl)dipyrromethane (not isolated), which upon condensation with a dipyrromethane in situ afforded a mixture including a trans-AB-porphyrin, A-porphyrins, and etioporphyrin (Scheme 1).
